Patients with cancer and chemotherapy-induced neutropenia are at risk for severe bacterial infections. This risk is not uniform among all cancer patients but is dependent primarily on the depth and duration of neutropenia and the type of underlying disease. Accordingly, the decision whether to use antibacterial prophylaxis to prevent serious infections in these patients requires a balance between expected benefit and the risks for infection, adverse drug-related events, and emergence of antibiotic resistance. Although antibacterial prophylaxis has the potential to benefit all patients with chemotherapy-induced neutropenia, the benefit regarding reduction in documented infections has been firmly established only in patients with neutropenia expected to exceed 7 days. A recent meta-analysis showed enhanced survival in patients receiving antibacterial prophylaxis during neutropenia; most patients enrolled in the analyzed trials had a hematologic malignancy. Among patients with neutropenia at lower risk for infectious complications (a category that includes most patients with solid tumor malignancies), the main benefit of antibacterial prophylaxis relates to a reduction in fever rather than documented infections. The authors advise quinolone prophylaxis (levofloxacin is preferred), in patients with an expected duration of neutropenia (absolute neutrophil count < 1000/μL) of more than 7 days. Trimethoprim-sulfamethoxazole should be used in patients at risk for Pneumocystis jiroveci (formerly P carinii), such as childhood acute lymphoblastic leukemia. In patients with neutropenia expected to last 7 days or less and not receiving immunosuppressive regimens (e.g., systemic corticosteroids), the authors recommend no initial prophylaxis. However, if such patients develop fever during neutropenia, they should be considered for outpatient empiric therapy with an oral quinolone–containing regimen if they meet criteria for low risk for complications.